Pathophysiology of Fetal
and Neonatal Kidneys
Farid Boubred and Umberto Simeoni
Abstract
Fetal renal development is a complex phenom-
enon. The ureteric bud and metanephric mesen-
chyme interaction is essential for nephrogenesis
which results from the expression of specific
genes, the fetal environment, or the interaction
of both factors. IUGR, maternal diabetes, mater-
nal undernutrition, micronutrient deficiency, and
fetal or neonatal exposure to drugs (NSAIDS,
ACE-Is, glucocorticoids, aminoglycosides) or to
toxic (alcohol) are known to affect
nephrogenesis. After a brief review of fetal and
neonatal renal physiology, pathologic situations
including preterm birth, congenital anomalies of
the kidney and urinary tract, kidney diseases,
and kidney-pharmacology interactions will be
developed. Renal maldevelopment and expo-
sure to factors that can alter the fetal and neona-
tal renal functions and structure increase the risk
of hypertension and chronic renal disease in
adulthood. Long-term follow-up is thus required
and early markers of nephron dosing and renal
injury should be developed with the aim to
implement preventive strategies.
F. Boubred
Division of Neonatology, La Conception Hospital,
Marseille, France
e-mail: farid.boubred@ap-hm.fr
U. Simeoni (*)
Division of Pediatrics, CHUV & UNIL, Lausanne, Vaud,
Switzerland
e-mail: Umberto.simeoni@chuv.ch
# Springer International Publishing AG 2018
G. Buonocore et al. (eds.), Neonatology,
https://doi.org/10.1007/978-3-319-18159-2_261-2
Contents
Kidney Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Renal Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
The Fetus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Glomerular Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Tubular Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
The Newborn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
The Immature Kidney . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Congenital Tubulopathies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Parenchymal Consequences of Urinary Tract
Anomalies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Pharmacological Interactions . . . . . . . . . . . . . . . . . . . . . . . . . 10
Long-Term Consequences of Nephron Number
Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Salient Points
• Fetal renal development starts with an interac-
tion between the ureteric bud and metanephric
mesenchyme and an interaction between the
expression of specific genes and the fetal
environment.
• During intrauterine life, the placenta is respon-
sible for fetal homeostasis. Glomerular filtra-
tion rate, renal blood flow, and tubular
functions increase with renal growth and
nephrogenesis. The formation of the urine,
the main component of amniotic fluid in the
third trimester, begins by 12 weeks of gesta-
tion. Urine production is essential for fetal
well-being, the promotion of lung growth,
1
2 F. Boubred and U. Simeoni
and in hormonal production (1.25 OH vitD3
and erythropoietin). Urine flow increases ten-
fold from 6 ml/h at 20 weeks to 60 ml/h at 40
weeks of gestation. At near-term, the fetal kid-
ney shows sufficient glomerular and tubular
development to allow for adaptation to extra-
uterine life.
• Serum creatinine is used to assess glomerular
filtration rate in neonates.
• At birth, the final nephron number varies from
500,000 to 1 million per kidney. Such variation
in nephron number is due to genetic factors, the
fetal environment, or a combination of both.
Intrauterine growth restriction, maternal diabe-
tes, maternal undernutrition, micronutrient
deficiency, and fetal or neonatal exposure to
drugs (NSAIDS, ACE-Is, glucocorticoids,
aminoglycosides) or toxins (alcohol) affect
nephrogenesis.
• In preterm infants, nephrogenesis is incom-
plete at birth and may be altered in preterm
infants.
• Congenital tubular diseases are rare. Bartter
syndrome (characterized by salt wasting,
hypovolemia, hyper-reninemia, and metabolic
alkalosis) is a group of tubulopathies that
involve the regulation and expression of vari-
ous tubular transporters located in the ascend-
ing limb of Henle and the corresponding genes
(upregulation of NKCC2 and ROMK and
downregulation of Barttin and ClC-Kb).
Bartter syndrome (polyhydramnios and hyper-
calciuria) is seen in fetal and neonatal forms.
Treatment consists of salt adaptation, water
and potassium intake, and amiloride and/or
indomethacin use.
• Congenital abnormalities of the kidney and
urinary tract (CAKUT) are a range of anoma-
lies including malformations of ureteropelvic
junction, of vesicoureteric junction, or of
vesicourethral area and dysplastic kidneys.
• Renal maldevelopment and exposure to factors
that can alter fetal and neonatal renal functions
and structure increase the risks of hypertension
and chronic renal disease in adulthood. Long-
term follow-up is thus required and early
markers of nephron dosing and renal injury
should be developed with the aim of
implementing preventive strategies.
Kidney Development
The definitive kidney, the metanephros, is formed
by two processes: nephrogenesis (formation of
glomerulus and tubules) and branching morpho-
genesis (formation of collecting ducts, calyces,
pelvis, and ureter). The metanephric kidney
takes place after the formation and involution of
two embryonic kidneys, the pronephros (non-
functional organ) and mesonephros (first func-
tional kidney), that in turn evolves into the
ureteric bud (UB). The metanephros appears in
the fifth gestational week and develops from the
specific interaction of the epithelial UB and the
undifferentiated metanephric mesenchyme (MM).
This interaction is crucial for the differentiation of
mesenchyme and the induction of UB branching
division (Fig. 1). The UB undergoes branching
morphogenesis and invades the MM in response
to signals elaborated by the mesenchymal cells.
This process gives a 15 branch generation. At
20–22 weeks of gestation, branching morphogen-
esis is completed and will result in the collecting
system. Mesenchymal cells that are in close con-
tact with the invading UB undergo an epithelial
transformation. The induced MM gives the neph-
rons through the consecutive stages of condensa-
tion, renal vesicle, vascular cleft, and S-shaped
body. The nephrons develop in successive stages
from the inner to the outer area of the kidney in
parallel with the vascular system. The glomerular
capillary tuft is formed via recruitment and prolif-
eration of endothelial and mesangial cell precur-
sors. In human, the primitive glomerulus appears
at approximately 9–10 weeks of gestation.
Nephrogenesis is completed by 34–36th weeks
of gestation with about 60% of the nephrons
being formed during the third trimester of preg-
nancy (Saxen 1987; Merlet-Benichou et al. 1999).
Once nephrogenesis is complete, stroma cells dif-
ferentiate into fibroblast-, pericyte-, and
lymphocyte-like cells. At birth the final nephron
varies from 500,000 to 1 million per kidney. Such
variation in nephron number is due to genetic
Pathophysiology of Fetal and Neonatal Kidneys 3

Fig. 1 Kidney
development: simplified Nephron deficit
schematic process of CAKUT
normal and pathologic
kidney development
Abnormal stromal
Abnormal Csyts development
Branching development Nephrogenesis failure (metaplasic tissue)

Genes
Fetal environment
Drugs, toxic
Urinary obstruction

Ureteric bud Metanephric mesenchyme

Branching Nephrogenesis
morphogenesis (epithelial differentiation)

Collecting duct system Nephron Stroma tissue

Kidney and Urinary tract

factors, to the fetal environment, or to a combina-

tion of both (Chevalier 1996). Several genes and
molecular pathways control the formation of the
renal collecting system and nephrogenesis, such
as transcriptional factors (PAX-2, WT1), growth
factors (IGF, EGF, TGF, GDNF, FGF), onco-
genes, extracellular matrix, and vascular factors
(Table 1) (Burrow 2000). These factors act at a
specific time of kidney development especially
when the UB interacts with the adjacent
MM. For instance, blockade of VEGF receptor,
inhibition of the renin-angiotensin system (RAS),
and knockout mice for COX-2 gene expression
are associated with impaired nephrogenesis
including glomerular cysts, dysplastic tubules,
and tubular dysgenesis (Dinchuk et al. 1995;
McGrath-Morrow et al. 2006; Pryde et al. 1993).
Renal Physiology
The Fetus
During intrauterine life, the homeostasis of the
fetus is assigned to the placenta. Glomerular fil-
tration rate, renal blood flow, and tubular func-
tions progress with renal growth and
nephrogenesis. The kidney is involved in urine
production which is essential in fetal well-being
and in hormonal production (1.25 OH vitD3 and
erythropoietin). The formation of the urine, the
main component of amniotic fluid in the third
trimester, begins by 12 weeks of gestation. The
urinary flow rate increases tenfold from 6 ml/h at
20 weeks to 60 ml/h at 40 weeks of gestation,
which expresses an optimal structural and func-
tional renal development. In the near-term period,
the fetal kidney shows sufficient glomerular and
4 F. Boubred and U. Simeoni

Table 1 Syndromes and gene defects associated with abnormal kidney development (CAKUT)
Syndrome Gene defects Kidney malformations
Renal-coloboma syndrome PAX 2 Hypoplasia, VUR
Renal cysts and diabetes syndrome HNF1b Dysplasia, hypoplasia
Branchio-oto-renal syndrome EYA1, SIX1 Unilateral or bilateral agenesia/
dysplasia
Renal tubular dysgenesis RAS components Tubular dysplasia/dysgenesis
Campomelic dysplasia SOX9 Dysplasia, hydronephrosis
Townes-Brocks syndrome SALL1 Dysplasia, hypoplasia, VUR
Simpson-Golabi-Behmel syndrome GPC3 Medullary dysplasia
Kallmann syndrome KAL1,FGFR1, PROK Renal agenesis
Fraser syndrome FRAS1 Dysplasia, renal agenesis
Alpert syndrome FGRG2 Hydronephrosis
Alagille syndrome JAGGED1 Cystic dysplasia
Meckel-Gruber syndrome MKS1,MKS3 Cystic renal dysplasia
Hypoparathyroidism, deafness, and renal anomaly GATA3 Dysplasia, VUR
syndrome (HDR)
DiGeorge syndrome 22q11 Agenesia, dysplasia, VUR
Beckwith-Wiedemann syndrome P57 Dysplasia
Pallister-Hall syndrome GLI3 Dysplasia
Nail-patella syndrome LMX1B Agenesia, glomerular anomalies
Smith-Lemli-Opitz syndrome 7 hydroxy-cholesterol Agenesia, dysplasia
reductase
Zellweger syndrome PEX1 Cystic dysplasia, VUR
Glutaric aciduria type II Glutaryl CoA Cystic dysplasia
dehydrogenase
STAR syndrome FAM58A CAKUT
Hypothyroidism PAX8 Renal agenesis
– SOX17, DSTYK, BMP4 CAKUT

tubular development to allow the adaptation to
extrauterine life (Brophy and Robillard 2004).
Glomerular Function
During fetal life, the glomerular filtration rate
(GFR) increases progressively, while renal vascu-
lar resistances (RVRs) remain elevated. The fetal
GFR is mainly driven by nephrogenesis. Systemic
blood pressure, around 40–60 mmHg, and renal
blood flow are low in comparison with the new-
born or the adult. For instance, in sheep, the fetal
kidneys receive 3% of cardiac output compared to
15% in the neonatal period. Low RBF is associ-
ated with elevated RVRs. This state is due to a
subtle equilibrium between vasoconstrictive fac-
tors including the renin-angiotensin system
(RAS) and renal sympathetic nervous system
and vasorelaxing factors such the prostaglandins,
nitric oxide, and other factors (Fig. 2). Highly
expressed during the active development of the
kidney, these vasoactive factors participate to
nephrogenesis and in the regulation of intrarenal
vascular blood flow (essential for the develop-
ment as well).
In the fetal kidney, the RAS is the principal
vasoconstrictive factor; it is upregulated during
active nephrogenesis and downregulated at the
end of this process. The RAS maintains renal
blood flow and renal pressure perfusion. The
fetus is able to release renin into the fetal circula-
tion. Renin does not cross the placenta and the
fetal plasma renin levels are higher than maternal
levels. Angiotensin II increases mainly the glo-
merular efferent tone which is highly sensitive to
angiotensin. Renal sympathetic nervous system
increases renal vascular tone, in afferent and
Pathophysiology of Fetal and Neonatal Kidneys
Prostaglandins
aa CHP
NO
Kinins
ANP
Vasoconstriction
Vasodilatation
Fig. 2 Determinants of glomerular filtration with preglomerular and postglomerular vasoactive forces
efferent arteriole. The fetal renal vasculature is
more sensitive to alpha2-adrenoreceptor stimula-
tion than the neonatal one. Upregulation of
alpha2-receptors is associated with down-
regulation of beta2-adrenoreceptors. Adenosine
vasodilates glomerular arterioles in physiologic
state but increases tone of afferent glomerular
arterioles in stress conditions, responsible for
reduced GFR.
Vasoconstrictive forces are counterbalanced by
vasodilating factors that principally act on the
glomerular afferent arteriole to maintain a suffi-
cient renal blood flow. Prostaglandins, nitric oxide
(NO), and kallikrein-kinin system are principal
factors. Prostaglandins, in particular E2 and I2,
are of major importance. These prostaglandins are
produced by the placenta, membranes, and the
fetus, from the action of two enzyme isoforms,
the cyclooxygenase types 1 and 2 (COX-1 and
COX-2), and their production is stimulated by
angiotensin II (34). COX-2 is constitutive in
fetal kidney and appears essential for the devel-
opment and function of the kidney (Khan et al.
2001). Administration of COX inhibitors during
pregnancy decreases renal blood flow, impairs
renal function, and induces oligohydramnios.
Nitric oxide is synthetized by endothelial cells
5
Angiotensin II
BSHP ea
Norepinephrine
Endotheline
aa : Afferent arteriole
ea : Efferent arteriole
CHP: Corpuscular Hydrostatique Pressure
:Oncotic pressure
BSHP: Bowman Space Hydrostatic Pressure
and vasodilates the afferent arteriole. In sheep,
inhibition of NO increases renal vascular resis-
tance, impairs renal function, and reduces sodium
excretion. Other factors including endothelin and
atrial natriuretic factors modulate renal hemody-
namic as well.
Tubular Function
The tubular system has different secretion and
reabsorption activities depending on the tubular
segment. For example, the proximal tubule is
principally involved in regulation of fluid, elec-
trolytes, amino acids, glucose, and the distal
tubules and collecting system in fluid and tonicity
regulation. Tubular transporters mature differ-
ently during the development of the nephrons.
Distal tubular phosphorus and potassium channels
mature early to make them available for cellular
functions. These features are responsible in part
for higher fetal plasma potassium and phosphorus
levels than in the mother. Renal tubules are the
target of hormones including RAS, aldosterone,
prostaglandins, atrial natriuretic peptide, and cor-
tisol (maturational effect). The sensitivity of renal
tubules to such hormones matures progressively
6 F. Boubred and U. Simeoni
along gestation. Finally the relative tubular imma-
turity associated with hypotonic urines
(100–250 mOsm/kg H2O) allows the production
of amniotic fluid at a sufficient rate which is
essential for fetal well-being (Brophy and
Robillard 2004).
The excretion of sodium is high during fetal
life but decreases with renal development. This
state is related to various factors including high
circulating sodium concentrations and high sensi-
tivity to natriuretic factors, large extracellular
fluid volume, relative insensitivity to hormonal
factors, and dysmaturity of tubular sodium
reabsorption. In opposition with adult physiology,
the sodium is mainly reabsorbed in the distal
portion of the immature tubules. The sodium/
hydrogen exchangers (NHE, four different iso-
forms) play an important role. These exchangers
mediate the exchange of one sodium for one
hydrogen and contribute to the acidification of
urine. The NHE three channel, located at the api-
cal or luminal membrane of tubular cells, is
thought to be responsible for the bulk of tubular
reabsorption of sodium. It is downregulated in the
proximal portion of the immature tubules when it
is markedly upregulated after birth. Its expression
and activity are dependent on tubular Na+, K+-
ATPase which is downregulated in immature kid-
ney (Hoster 2000).
The balance of potassium is positive in the
fetus, due to active transplacental transfer and
renal immaturity. They both make potassium
available for cell growth and cell functions.
Renal secretion is low and tends to increase
toward term. Potassium excretion increases with
glomerular and tubular surface area, with matura-
tion of tubular Na+, K+-ATPase activity, and with
the progressive tubular sensitivity to aldosterone.
As for potassium, the fetus is characterized by
a positive phosphorus balance resulting from a
transplacental transport against a concentration
gradient, a high rate of tubular reabsorption via a
sodium-phosphorus co-transporter, and a relative
parathyroid insufficiency. Calcium is important
for the adequate mineralization, growth, and
fetal skeleton. Vitamin D-dependent calcium-
binding proteins, involved in transepithelial cal-
cium transfer, are present in fetal kidney.
However, the major role of the kidney in fetal
calcium homeostasis is the production of 1.25
(OH)2D3 rather than renal regulation of calcium
excretion.
During fetal development, the placenta regu-
lates the fetal acid-base balance. The reabsorption
of bicarbonates and chloride in the proximal
tubule increases with gestational age, which
allows the fetus to participate to acid-base homeo-
stasis, near term. This function is mainly related to
the maturation of the carbonic anhydrase activity.
The fetus produced hypotonic urine at an ele-
vated rate of 1.5 l every day. The urine concentra-
tion capacity is blunted in the immature kidney.
This defect is related to various factors including a
low sensitivity of the collecting duct to arginine
vasopressin (AVP), a structural immaturity of the
loop of Henle with preferential distribution of
blood flow to the inner cortex, a low gradient
concentration in the medulla due to limited pro-
tein intake to generate significant amounts of urea,
and a low expression of aquaporin 2 (AQ2). AQ2,
a water channel, is located in the apical membrane
of collecting duct cells and is involved in water
reabsorption. Humans who lack aquaporins
(AQs) have a urinary concentrating defect.
Expression of AQs is regulated by the AVP via
the V2 receptor. AVP is highly synthesized during
the last trimester in pregnancy (Nielsen and
Frokaier 2002). The immaturity of tubular func-
tions and its maturation explain the high rate of
amniotic fluid production which decreases at the
end of gestation.
The Newborn
Glomerular Function
After birth hemodynamic changes (increased
blood pressure and renal blood flow) and struc-
tural changes contribute to postnatal maturation of
GFR. As nephrogenesis is terminated at birth,
postnatal structural change is based on the matu-
ration of preexisting renal structures. This process
includes increase in glomerular membrane perme-
ability, in corpuscular glomerular diameter (espe-
cially of glomeruli from the outer area of cortex),
in filtration surface area, and in intrarenal
Pathophysiology of Fetal and Neonatal Kidneys
redistribution of blood flow. Glomerular size
reaches adult values at the age of 3 years. These
structural changes result in enhanced filtration
surface area.
Transition of fetal circulation to extrauterine
life is characterized by a rapid increase in systemic
blood pressure and renal blood flow. The rapid
change in RBF is associated with postnatal
decrease in renal vascular resistances (decrease
in glomerular vasoconstriction). Glomerular cap-
illary hydrostatic pressures increase as well but
remain lower than in the adult (Solbaug and Jose
2004).
After birth GFR rapidly increases (2.5- to
threefold increase) from 20 ml/min/1.73 m2 to
half of adult values at the end of the neonatal
period (Guignard 1975). In preterm infants GFR
correlates with gestational and is at birth less than
15 ml/min/1.73 m2. Postnatal maturation depends
on gestational age with a delayed maturation
being possibly observed in very low birth weight
infants (Gubhaju et al. 2014). In term infants,
plasma creatinine concentrations are elevated at
birth (60–70 mcmol/l) and stabilize at the end of
the first week (30–40 mcmol/l). In preterm
infants, creatinine levels are elevated on the first
day (90–110 mcmol/l), increasing transiently
within days 3–5 (reaching 130–150 mcmol/l)
and then decrease progressively (Gallini et al.
2000). Neonates and especially preterm infants
are in a state of physiologically renal insuffi-
ciency. A delicate balance of vasoconstrictor and
vasodilator forces which maintains GFR and
immature renal structure makes newborn and
especially preterm infants at high risk to develop
renal dysfunction in specific conditions (hypoten-
sion, hypovolemia, perinatal asphyxia, and neph-
rotoxic drugs).
Serum creatinine is widely used to assess glo-
merular filtration rate (GFR) in neonates. Clear-
ance of endogenous creatinine can be used in
clinical practice and needs strict 12–24-h urine
collection which can be difficult in preterm
infants. Creatinine is a metabolite of creatine
located in skeletal muscle and is filtered and
secreted in part by renal tubular cells. Muscle
mass influences serum creatinine levels. Other
markers of GFR including inulin, cystatin C, and
7
beta trace protein are not used routinely in neo-
nates. Clearance of inulin is the gold standard to
evaluate GFR. Inulin is inert, being not metabo-
lized and neither reabsorbed nor secreted by the
renal tubules; however, it has limited applications
in clinical practice. Cystatin C is produced by all
nucleated cells and is independent of muscle
mass. It is freely filtered and reabsorbed but catab-
olized in the kidney, which prevents clearance
measurement. Serum levels are high during the
neonatal period and stabilize at 12 months of age.
Cystatin C and beta trace protein are being evalu-
ated in newborn and preterm infants. Current data
consider cystatin C as a valuable tool to assess
GFR in newborn and preterm infants (Filler et al.
2016).
Tubular Function
The postnatal maturation of renal tubules follows
the maturation of GFR. Postnatal maturation is
characterized by a tenfold increase in proximal
tubular length and diameter within the weaning
period.
After birth, the regulation of homeostasis is
transferred from the placenta to the kidney. Post-
natal fluid and electrolytic adaptation is character-
ized by a transient increase in diuresis during the
first week of life due to the contraction of the
extracellular volume. Commonly neonates lose
around 5–10% of their birth weight. Very low
birth weight may undergo a higher weight loss
of up to 15% of their birth weight. Fractional
excretion of sodium in neonates is around 1%
and decreases progressively in relation to a rapid
maturation of proximal tubules. Fetal exposure to
glucocorticoids at the end of gestation accelerates
the maturation of tubular transporters (NHE, Na+,
K+-ATPase, etc.) (Brophy and Robillard 2004).
The neonate is able to achieve maximal dilu-
tion with urine osmolarity as low as 40–60 mOsm/
l. Diluting capacity tends to mature rapidly in the
newborn and in the preterm infant who at 36th
postconceptional age have the same dilution
capacity than adult. Within the limits allowed by
of GFR, neonates, even preterm infants, tolerate a
large range of fluid intakes (150 ml/kg/day) with-
out major alterations in water and electrolyte
parameters. Diluting capacity is greater than
8 F. Boubred and U. Simeoni
Fig. 3 Renal mechanism
of systemic hypertension Maternal
nutritional status
and renal damage, the
“Brenner hypothesis”
IUGR
Preterm birth ?
Single nephron
glomerular filtration rate
(SNGFR)
concentrating capacity, which is limited to
400–600 mOsm/l. Children reach the adult maxi-
mal urine concentration ability
(1300–1400 mOsm/kg) by 2 years of age. This
characteristic may be explained by reduced tonic-
ity of the medullary interstitium, low expression
of water channels (aquaporins), and relative tubu-
lar insensitivity to ADH. Higher production of
prostaglandin E2 in neonate may inhibit the tubu-
lar effect of ADH. Low neonatal concentrating
capacity is of limited importance in healthy neo-
nates. However, neonates and especially preterm
infants are more vulnerable to insufficient water
intakes and extrarenal water loss (skin losses,
diarrhea, etc.) with the risk of hypernatremic
dehydration and osmotic diuresis and favored by
a lower threshold for renal glucose excretion.
The newborn has a diminished threshold for
bicarbonates. The large extracellular fluid (ECF)
volume expansion may result in depressed proxi-
mal tubular bicarbonate reabsorption. When ECF
is contracted, renal reabsorption increases and
urinary pH becomes more acidic. In preterm
infants, immaturity of carbonic anhydrase may
prolong the depressed tubular bicarbonate
reabsorption. The normal range for plasma bicar-
bonate concentration is lower in preterm infants
(16–20 mmol/l) than term infants (21–24 mmol/l).
Nephrotoxic Maternal gestational
drugs diabetes
Congenital renal
Reduced nephron number anomalies
Filtration surface area
Arterial
blood pressure
Glomerular hypertension
Proteinuria
Glomerulosclerosis
Pathophysiology
The Immature Kidney
In the preterm infants, nephrogenesis is incom-
plete at birth and has to continue in an unfit envi-
ronment. Nephrogenesis may be altered in
preterm infants (Rodriguez et al. 2004; Sutherland
et al. 2011). Experimental studies show discordant
findings (Stelloh et al. 2012; Gubhaju et al. 2009).
In rodents only one study has shown reduced
nephron endowment in pups born preterm
(Stelloh et al. 2012). Such a finding has not been
found in preterm baboon (Gubhaju et al. 2009).
The degree of immaturity may explain such dis-
cordant findings. In contrast with the baboon
model, preterm birth occurred during the early
stage of nephrogenesis in the rodent models.
These findings suggest that extremely preterm
infants are at high risk of reduced nephron endow-
ment. Data are limited in preterm infants; autopsy
findings have shown an alteration of glomerular
structure and acceleration of nephron maturation
with a possibly reduced nephron endowment
(Rodriguez et al. 2004; Sutherland et al. 2011).
Impairment of mesenchymal cell differentiation
has been suggested. Moreover it is not excluded
Pathophysiology of Fetal and Neonatal Kidneys 9

Cinulin
60
Term

40 Premature

70 20

60 Days
C inulin , ml/min per 1.73m2

5 10 15 20
50

40

30

20

10

2 4 6 8 10 12 14 16 18 20 22 24 26
Postnatal age, days

Fig. 4 Postnatal glomerular filtration rate in neonates (C inulin: inulin clearance) (From Guignard et al. 1981)

that environment factors to which preterm infants inhibitors (indomethacin) for closure of a patent
face up during the neonatal period including ductus arteriosus impairs renal function, leads to
infection/inflammation, oxidative stress, nephro- oliguria, and reduces RBF and GFR. Ibuprofen,
toxic drug use, or undernutrition can influence another COX inhibitor, has moderate renal
nephrogenesis and thus nephron endowment. For effects. However, these adverse renal effects can
instance, neonatal undernutrition has been shown be prolonged up to 1 month and can limit renal
to be associated with reduced kidney volume excretion of some medications (Giniger et al.
(a surrogate of nephron mass) in infants born 2007; Vieux et al. 2011). In animal, neonatal
preterm (Bacchetta et al. 2009). Collectively the indomethacin administration results in reduced
current findings suggest that the extremely pre- nephron number in adult rats unlike ibuprofen
term infants and preterm infants exposed to (Kent et al. 2014).
adverse neonatal complications have a high risk Postnatal hydro-electrolytic adaptation is char-
of nephron deficit. acterized by an excessive water and sodium losses
In comparison with term neonates, GFR is during the first 10 days after birth. Preterm infants
lower in preterm infants and increases progres- are prone to water and salt wasting with high risk
sively after birth (Gubhaju et al. 2014; Bueva of early hypernatremia and late hyponatremia.
and Guignard 1994) (Figs. 4, 5 and 6). Structural Fractional excretion of sodium is elevated in pre-
maturation drives the progressive maturation of term infants (5% vs <1% in term infants) and
GFR in very preterm infants in whom postnatal reaches term values progressively after days
nephrogenesis continues after birth. Blood pres- 15–21. A postnatal contraction of the extracellular
sure and renal blood flow are low in preterm fluid volume occurs during the first postnatal days
infants. The RVRs are high and the RAS and translates into a 2–3% daily weight loss. The
upregulated. The immature kidney is particularly optimal maximum weight loss is unknown; a
dependent on vasodilator forces to maintain a maximum limit of 10–15% total weight loss is
sufficient GFR. Administration of prostaglandin common especially in extremely preterm infants
10
70
Creatinine clearance, ml/min × 1.73m2
60
50
40
30
20
10
0
0 1-2
Fig. 5 Postnatal maturation of glomerular filtration rate in term and preterm infants (Bueva and Guignard 1994)
and should be not exceeded. Fluid and electrolyte
balance has to be thus closely followed up and
adapted. Moreover, the kidney of preterm infants
cannot efficiently excrete excessive water and
sodium loads which increase the risk of
bronchopulmonary dysplasia, intracerebral hem-
orrhage, and necrotizing enterocolitis. It is com-
mon to introduce sodium, potassium, and
phosphorus by postnatal day 2 and to adapt indi-
vidually electrolyte intake (especially sodium).
However, nutritional practices have recently
changed with early introduction of high protein
and caloric intakes, which stimulates anabolism
and prevents early catabolism. This new nutri-
tional strategy enhances cellular use of potassium
and phosphorus and increases the risk of early
hypokalemia and hypophosphatemia especially
in intrauterine growth restricted preterm infants
(Boubred et al. 2015). Potassium and phosphorus
intake can be thus introduced early from birth
onwards for some infants. Rapid growth induces
sodium cell utilization and together with sodium
wasting favors the occurrence of late hypo-
natremia. Fluid, minerals, and electrolyte balances
should be adapted tightly and individualized to
promote optimal growth and deficiency (Boubred
F. Boubred and U. Simeoni
1000-1500g
1501-2000g
2001-2500g
term
8-9 15-16
Age, days
et al. 2015; Sweet D and the working group on
prematurity 2007). Glomerular and tubular conse-
quences of immaturity are shown in Table 2.
Preterm infants are more likely to receive drugs
in neonatal intensive care unit. Most drugs are
eliminated by the kidney and undergo glomerular
filtration or tubular metabolism both being imma-
ture in preterm infants. Circulating levels of drugs
such as vancomycin or aminoglycosides need to
be monitored to optimize dosage and to reduce
toxicity.
Glomerular and tubular consequences of pre-
maturity are blunted by maternal administration of
synthetic glucocorticoids (GCs) (betamethasone
and dexamethasone). Prenatal administration of
GC improves systemic blood pressure, RBF, and
GFR and accelerates the maturation of tubular
functions with enhanced proximal reabsorption
of sodium and excretion of potassium. This treat-
ment limits dysnatremia and hyperkalemia events
in preterm infants. Increased expression and activ-
ity of sodium exchanger, Na+, K+-ATPase activ-
ity, and renal sympathetic nerve activity are
involved (Catarelli et al. (2002).
Pathophysiology of Fetal and Neonatal Kidneys 11

150,0
140,0
GA <27 wks
Serum Creatinine (mmol/l) 130,0
GA 27-28 wks
120,0 GA 29-30 wks
110,0 GA 31-32 wks
100,0
90,0
80,0
70,0
60,0
50,0
40,0
30,0
0 1 2 3 4 5 6 7 10 17 24 31 38 45 52
Days of life
45,0
GA <27 wks
Creatinine Clearance (ml/min/1.73 m2)

40,0
GA 27-28 wks
35,0 GA 29-30 wks
30,0 GA 31-32 wks

25,0

20,0

15,0

10,0

5,0

0,0
3 7 10 17 24 31 38 45 52
Days of life

Fig. 6 Postnatal maturation of glomerular filtration rate in extremely low gestational age neonates (Gallini F et al.
Pediatre Nephrol 15:119–124)

Congenital Tubulopathies consists of salt adaptation, water and potassium

intake, and amiloride and/or indomethacin use.
Congenital tubular diseases are rare and include Primary pseudo-hypoaldosteronism is an auto-
various diseases according to defect in epithelial somal recessive disease due to defective epithelial
tubular channels (Rodriguez-Soriano 2000). ENaC channel (in collecting ducts). This syn-
Bartter syndrome is a group of tubulopathies drome is characterized by life-threatening salt
involving the regulation and expression of various wasting, risk of dehydration and arterial hypoten-
tubular transporters located in the ascending limb sion, severe hyperkalemia, distal tubular acidosis,
of Henle and the corresponding gene and hyperaldosteronism. This disease is treated by
(upregulation of NKCC2 and ROMK and down- sodium supplementation. When ENaC activity is
regulation of Barttin and ClC-Kb). Bartter syn- increased, sodium reabsorption is exaggerated
drome is characterized by salt wasting, by with hypertension and metabolic hypokalemia.
hypovolemia with a low or conserved blood pres- Renin activity and aldosterone levels are
sure, by hyper-reninism, and by metabolic alkalo- decreased. Liddle syndrome, an autosomal domi-
sis. Polyhydramnios and hypercalciuria are often nant disease, displays such features. Treatment
observed in fetal and neonatal forms. Treatment consists in salt restriction and amiloride.
12 F. Boubred and U. Simeoni

Table 2 Glomerular and tubular consequences of immature kidney

Fluid-electrolytes therapy in
preterm infantsa
D1–D2:
Volume: 80–100 ml/kg/d
Na: 0
K: 0 (except if
<3.5 mmol/l)
D3–D5:
Volume: 120–140 ml/kg/d
Na: 2–4 mmol/kg/d
K: 1–2 mmol/kg/d
D5:
Volume: 140–170 ml/kg/d
Na: 4–6 mmol/kg/d
K: 1–3 mmol/kg/d
a
Fluid, micronutrient, and electrolyte intakes are individually adapted
Glomerular immaturity:
consequences
Reduced ability to salt/water
overload excretion
Hyperkalemia
High sensitivity to vasoactive
drugs
Increased risk of renal failure
Reduced clearance of drugs
Tubular immaturity: consequences
Sodium wasting
Metabolic acidosis
Reduced urine concentration capacity with
conservative urine dilution capacity
Glycosuria
Elevated urinary calcium excretion
High sensitivity to diuretics

Nephrogenic diabetes insipidus, an X-linked or such a situation. In human, congenital

autosomal transmitted disease, is characterized by
polyuria-polydipsia, dehydration, irritability, and
failure to thrive. These symptoms are due to a
defect in the arginine vasopressin-V2 receptor or
in AQ2.
Parenchymal Consequences of Urinary
Tract Anomalies
Congenital abnormalities of the kidney and uri-
nary tract (CAKUT) are a wide range of anoma-
lies including malformations of ureteropelvic
junction, of vesicoureteric junction, or of
vesicourethral area and dysplastic kidneys.
Renal Structure Changes
The pathophysiological mechanism of CAKUT
remains unknown. One can postulate that urinary
obstruction affects the interaction UB-MM with
failure in the induction of metanephrogenic blas-
tema. After an early compliance stage, obstruction
of the collecting system induces urinary hyper-
pressure and muscular hypertrophy. In fetal
lamb, early and complete ureteral obstruction
impairs renal architecture with abnormal tubular
differentiation, inflammation, and reduced neph-
ron endowment. Changes in renal expression of
transcription factors (Pax2, Wnt) involved in early
stage of nephrogenesis have been demonstrated in
ureteropelvic junction obstruction is associated
with renal histologic changes including decreased
glomerular density, interstitial fibrosis, and tubu-
lar dilatation (Peters et al. 1992).
A genetic and developmental mechanism has
been proposed for CAKUT. Various defects in
specific genes involved in renal development
affect kidney parenchyma and urinary tract devel-
opment (few examples in Table 1). However, the
pathogenesis of this syndrome is multifactorial
and involves single nucleotide variants and epige-
netic mechanism through which environment can
impair the development of the kidney and urinary
tract (Nicolaou et al. 2015). The quality of the
ureteric bud-mesenchymal interaction, the posi-
tion at which arises the UB from the pronephros,
and the number of branching morphogenesis are
critical for the kidney development. Failure of
induced ureteric bud outgrowth leads to renal
agenesis. An aberrant outgrowth of more than
one UB may result in double collecting system
and duplication of the ureter. An ectopic position-
ing of the UB is associated with renal tissue mal-
formation, abnormalities of the ureterovesical
junction, and a nephron deficit related to reduced
branching morphogenesis (Fig. 1).
Renal Function Changes
The outcome of CAKUT depends on the impor-
tance of urinary obstruction, on the kidney
Pathophysiology of Fetal and Neonatal Kidneys
structure, on fetal renal functions
(oligohydramnios, urinary sodium concentra-
tions, fetal beta2-microglobulin), and on defects
in other organs. Early occurrence of urinary tract
obstruction, bilateral renal dysplasia, reduction of
the kidney size, and oligohydramnios (a surrogate
of severe fetal renal insufficiency) is associated
with poor renal prognosis. Infants with severe
pathology often die in the perinatal period as a
consequence of Potter’s sequence (pulmonary
hypoplasia resulting from oligohydramnios and
fetal renal function insufficiency). Survivors may
develop renal failure during childhood. Dialysis
during neonatal period should be discussed with
parents and the multidisciplinary nephrology
team before and after birth.
Infants with severe obstructive nephropathy
are prone to acid-base and hydro-electrolytic bal-
ance abnormalities and to impaired GFR. Com-
plete and prolonged fetal ureteral obstruction is
associated with decrease RBF and GFR propor-
tional to loss of parenchyma. The RAS is
upregulated in such situations. Renal dysfunc-
tions lead to type IV renal tubular acidosis (hyper-
chloremic metabolic acidosis) with hyperkalemia,
salt wasting, and defect in urine concentration
responsible for water wasting and nephrogenic
diabetes insipidus. Various changes in tubular
channel exchanger, decreased NA+, K+-ATPase
activity, unresponsiveness of the damaged distal
nephron to aldosterone with secondary hyper-
aldosteronisme, loss of H+ ATPase on the surface
of intercalated cells, and downregulation of
aquaporins have been described. Treating and
preventing renal infection, adapting protein
intake, and limiting the use of or close monitoring
of nephrotoxic drugs aim to preserve renal
functions.
Pharmacological Interactions
The number of pregnant women and women of
childbearing age receiving drugs is constantly
increasing. These drugs can cross the placenta
and can impair potentially the function and struc-
ture of the fetal kidney. The newborn may in turn
express renal failure with various severities up to
13
neonatal death. Selective COX-2 inhibitors and
nonselective nonsteroidal anti-inflammatory
drugs (NSAIDs), ACE-Is, and AT1R antagonists
are the main drugs affecting the development and
the function of perinatal kidney [review 32].
Nonsteroidal anti-inflammatory drugs
(NSAIDs) can be used as antalgic or as tocolytic
agent in pregnant woman (indomethacin). The
renal side effects of in utero exposure to NSAIDs
vary from transient fetal oligohydramnios to
severe and lethal renal failure in babies. Quickly
after the initiation of indomethacin therapy, a sig-
nificant reduction of fetal urine production occurs.
This effect, frequent and transient in many cases,
is the basis of treatment of polyhydramnios. The
available information originates principally from
retrospective studies and indicates a rate of inci-
dence from 1.5% to 20%. Experimental and
human studies show that NSAIDs decrease fetal
GFR (consequence of renal blood flow reduction)
and increase urine osmolality (enhanced activity
of arginine vasopressin). The risk of neonatal
renal failure seems increasing with prolonged
and cumulate doses, short time period between
treatment and delivery, preexisting fetal distress,
and low birth weight. In addition to the changes of
renal functions, a singular renal nephrotoxicity
dysplasia attributable to NSAIDs has been
described: various degrees of ischemic injuries
and fibrosis of medullary area, cortical necrosis,
focal tubular and glomerular microcysts of devel-
oping nephron, loss of differentiation between
proximal and distal tubules, and decreased renal
mass. These lesions are associated with increased
expression of renin in the juxtaglomerular appa-
ratus. The severity of renal hypoperfusion induced
by NSAIDs may lead to irreversible glomerular
and tubular injuries. Such effects have been noted
recently after prenatal exposure to the selective
inhibitors of COX-2, new generations of NSAIDs,
proposed as an alternative to nonspecific NSAIDs
with the aim of preventing adverse side effects.
When administered during pregnancy, inhibi-
tors of the RAS (ACE-Is and AT1R antagonists)
can induce a variety of serious fetal complica-
tions, with a high degree of mortality rate. These
complications named angiotensin-converting
enzyme inhibitor fetopathy include intrauterine
14
growth retardation, profound fetal and neonatal
hypotension refractory to any treatment, renal
failure, oligohydramnios with limb deformities
and pulmonary hypoplasia, hypocalvaria, and
increased rate fetal loss. Renal histology shows
typically proximal tubular dysgenesis. Numerous
cases have been reported with a wide range of
adverse fetal and neonatal renal effects varying
from transient oligohydramnios (when treatment
was arrested rapidly) to severe (requiring perito-
neal dialysis) and lethal renal failure. The magni-
tude of these adverse renal effects cannot be
quantifiable precisely, but the risk increases by
chronic administration and the stage of fetal expo-
sure, especially during the second and third tri-
mester. In contrast, elective exposure in the first
trimester of gestation is not associated with an
enhanced risk of teratogenicity. When therapy is
interrupted rapidly before 2nd trimester, poor or
no adverse renal effects are noted.
Experimental studies have shown that maternal
antenatal administration of various drugs can
affect nephrogenesis in the absence of renal dys-
functions in the fetus and newborn infants. In
rodents and sheep, antenatal maternal administra-
tion of glucocorticoids (GCs) at a specific time of
pregnancy reduces nephron number and induces
hypertension in adult offspring. The mechanism
by which GCs alter the fetal kidney structure is
unclear. Several pathways are suspected. In utero
exposure to GC may (1) disturb cell differentia-
tion/proliferation ratio at the expense of reduced
proliferation, (2) reduce ureteric bud branching,
(3) alter gene expression of specific genes
involved in kidney development (GNDF),
(4) decrease renal AT1R and renin gene expres-
sion, or (5) alter epigenetic marks.
Maternal administration of cyclosporine A
(CsA) during gestation (E14–18, and E20–24)
affects fetal growth and nephrogenesis leading to
a permanent nephron deficit in rat offspring (aver-
age of 25–30%). CsA may block epithelial trans-
formation of the metanephric mesenchyme. In
human, outcome of infants exposed in utero to
CsA has not shown any changes of renal function
and morphology in childhood. But data are too
scarce, and long-term follow-up (the maximal age
F. Boubred and U. Simeoni
of follow-up was 7 years) is insufficient to con-
clude definitely on the side effects at adulthood.
Antenatal maternal administration of ampicil-
lin and aminoglycosides reduces nephron number
(20–30%) and induces hypertension in adult rat
offspring. Reduced nephron number results from
a defect in UB branching morphogenesis affecting
the first branching division. Administration dur-
ing the late stage of nephrogenesis does not
induce a nephron deficit. Other aminoglycosides,
such amikacin and netilmicin, have less adverse
renal effects. Antenatal maternal administration of
ampicillin is associated with 20% reduction of
nephron number in rat offspring; apoptosis mech-
anism of MM is the suspected. Such experimental
observations have not been found in human. Other
drugs, such as chlorambucil and antineoplastic
drugs, can impair renal development with urinary
tract malformation and renal agenesis.
In summary, in most cases, newborn do not
express clinical renal failure postnatally. How-
ever, experimental studies suggest that prenatal
exposure to certain drugs may decrease nephron
endowment. One must be careful in extrapolating
data from animal to human, since major interspe-
cies differences in renal sensitivity to drugs exist.
However, long-term follow-up of infants exposed
in utero to drugs is needed.
Long-Term Consequences of Nephron
Number Reduction
It is suspected for a long date, since the works of
Brenner et al. in the 1980s, that a reduced nephron
number increases the risk of hypertension and
chronic renal insufficiency in adulthood (Brenner
et al. 1988). Reduced nephron number is associ-
ated with renal changes including single nephron
glomerular filtration hyperfiltration (SNGHF) and
glomerular and tubular hypertrophy. Such hemo-
dynamic changes are responsible for glomerular
injury through increase in glomerular capillary
hypertension. Over a long time, a vicious cycle
takes place leading to glomerular sclerosis,
chronic renal insufficiency, and hypertension
(cf Fig. 3). In human, an inverse relationship has
been established between nephron number and
Pathophysiology of Fetal and Neonatal Kidneys
hypertension (Keller et al. 2003). However, this
relationship is complex and involves various fac-
tors such as nephron dosing and postnatal factors.
For instance, congenital agenesis, a situation of
severe nephron deficit, is associated with early
development of systemic hypertension and early
chronic renal insufficiency during infancy of ado-
lescent. It is postulated that a moderate nephron
deficit at birth is insufficient to induce long-term
cardiovascular and chronic renal diseases but con-
stitutes a factor of vulnerability when other post-
natal factors including early catch-up growth or
overfeeding accelerate the development of these
diseases (Boubred et al. 2013).
At birth the final nephron number varies from
500,000 to 1 million per kidney. Such variation in
nephron number is due to genetic factors, to the
fetal environment, or to a combination of both.
Various perinatal factors have been shown to
induce nephron deficit including intrauterine
growth restriction (IUGR), maternal nutrient defi-
ciency (vitamin A, iron depletion, zinc defi-
ciency), maternal protein or global nutrition
deficit, exposure to drugs (see above) or toxic
(alcohol), maternal and fetal stress, and maternal
gestational diabetes (Merlet-Benichou et al.
1999). Preterm birth with postnatal adverse envi-
ronment (postnatal denutrition, stress, exposure to
nephrotoxic drugs) and renal and urinary tract
malformations are associated with impaired
nephrogenesis which may lead to reduced neph-
ron endowment.
Such perinatal events are less likely to affect
renal functions during the neonatal period but
increase the susceptibility of hypertension and
chronic renal disease in adulthood. Long-term
follow-up is needed, with close assessment of
blood pressure and renal parameters (creatinine,
proteinuria) to prevent such adverse evolutive car-
diovascular and renal diseases. Future studies may
focus on the development of markers of nephron
number endowment and of early biomarkers of
SNGHF and renal injury with the aim to implement
preventive strategies).
15
References
Bacchetta J, Harambat J, Dubourg L et al (2009) Both
extrauterine and intrauterine growth restriction impair
renal function in children born very preterm. Kidney Int
76(4):445–452
Boubred F, Vendemia M, Garcia-Meric P et al (2006)
Effects of maternally administered drugs on the fetal
and neonatal kidney. Drug Saf 29:397–419
Boubred F, Saint-Faust M, Buffat C et al (2013) Develop-
mental origins of chronic renal disease: an integrative
hypothesis. Int J Nephrol 2013:346067. https://doi.org/
10.1155/2013/346067
Boubred F, Herlenius E, Bartocci M et al (2015) Extremely
preterm infants who are small for gestational age have a
high risk of early hypophosphatemia and hypokalemia.
Acta Paediatr 104:1077–1083
Brenner BM, Garcia DL, Anderson S (1988) Glomeruli
and blood pressure. Less of one, more the other. Am J
Hypertens 1:335–347
Brophy PD, Robillard JE (2004) Functional development
of the kidney in utero. In: Polin A, Fox W (eds) Fetal
and neonatal physiology, 3rd edn. W.B. Saunders Com-
pany, Philadelphia, pp 1229–1239
Bueva A, Guignard JP (1994) Renal function in preterm
neonates. Pediatr Res 36:572–577
Burrow CR (2000) Regulatory molecules in kidney devel-
opment. Pediatr Nephrol 14:240–253
Catarelli D, Chirico G, Simoni U (2002) Renal effects of
antenally and postnatally administered steroids. Pediatr
Med Chir 24:157–162
Chevalier RL (1996) Developmental renal physiology of the
low birth weight preterm newborn. J Urol 156:714–719
Dinchuk JE, Car BD, Focht RJ et al (1995) Renal abnor-
malities and an altered inflammatory response in mice
lacking cyclooxygenase 2. Nature 378:406–409
Filler G, Guerrero-Kanan R, Alvarez-Elías AC (2016)
Assessment of glomerular filtration rate in the neonate:
is creatinine the best tool? Curr Opin Pediatr 28
(2):173–179
Gallini F, Maggio L, Romagnoli C et al (2000) Progression
of renal function in preterm neonates with gestational
age 32 weeks. Pediatr Nephrol 15:119–112
Giniger RP, Buffat C, Millet V et al (2007) Renal effects of
ibuprofen for the treatment of patent ductus arteriosus
in premature infants. J Matern Fetal Neonatal Med
20:275–283
Gubhaju L, Sutherland MR, Yoder BA et al (2009) Is
nephrogenesis affected by preterm birth? Studies in a
non-human primate model. Am J Physiol Renal Physiol
297:F1668–F1677
Gubhaju L, Sutherland MR, Horne RS, Medhurst A, Kent
AL, Ramsden A, Moore L, Singh G, Hoy WE, Black
MJ (2014) Assessment of renal functional maturation
and injury in preterm neonates during the first month of
life. Am J Physiol Renal Physiol 307(2):F149–F158
Guignard JP (1975) Glomerular filtration rate in the first
three weeks of life. J Pediatr 87:268–272
16
Guignard JP, Gruskin AB, Norman ME (eds) (1981) Pedi-
atric nephrology. Martinus Nijhoff, The Hague
Hoster M (2000) Embryonic epithelial membranes trans-
porters. Am J Phys 279:F74–F52
Keller G, Zimmer G, Gerhard M et al (2003) Nephron
number in patients with primary hypertension. N Engl
J Med 348:101–108
Kent AL, Koina ME, Gubhaju L et al (2014) Indomethacin
administered early in the postnatal period results in
reduced glomerular number in the adult rat. Am J
Physiol Renal Physiol 307:F1105–F1110
Khan KNM, Stanfield KM, Dannenberg A et al (2001)
Cyclooxygenase-2 expression in the developing
human kidney. Pediatr Dev Pathol 4:461–466
McGrath-Morrow S, Choc C, Molls R et al (2006) VEGF
receptor 2 blockade leads to renal cyst formation in
mice. Kidney Int 69:1741–1748
Merlet-Benichou C, Gilbert T, Vilar J et al (1999) Nephron
number: variability is the rule. Causes and conse-
quences. Lab Investig 79:515–526
Nicolaou N, Renkema KY, Bongers EM et al (2015)
Genetic, environmental, and epigenetic factors
involved in CAKUT. Nat Rev Nephrol 11:720–731
Nielsen S, Frokaier J, Marples D et al (2002) Aquaporins in
the kidney: from molecule to medicine. Physiol Rev
82:205–244
Peters CA, Carr MC, Lais A et al (1992) The response of
the fetal kidney to obstruction. J Urol 148:503–509
F. Boubred and U. Simeoni
Pryde PG, Sedman AB, Nugent CE et al (1993)
Angiotensin-converting enzyme inhibitor fetopathy. J
Am Soc Nephrol 3:1575–1582
Rodriguez MM, Gomez AH, Abitbol CL (2004) Histomor-
phometric analysis of postnatal glomerulogenesis on
extremely preterm infants. Pediatr Dev Pathol 7:17–25
Rodriguez-Soriano J (2000) New insight into the patho-
genesis of renal tubular acidosis-from functional to
molecular studies. Pediatr Nephrol 14:1121–1136
Saxen L (1987) Organogenesis of the kidney. Cambridge
University Press, Cambridge
Solbaug MJ, Jose PA (2004) Postnatal maturation of renal
blood flow. In: Polin A, Fox W (eds) Fetal and neonatal
physiology, 3rd edn. W.B. Saunders Company, Phila-
delphia, pp 1243–1249
Stelloh C, Allen KP, Mattson DL et al (2012) Prematurity
in mice leads to reduction in nephron number, hyper-
tension, and proteinuria. Transl Res 159:80–89
Sutherland MR, Gubhaju L, Moore L, Kent AL, Dahlstrom
JE, Horne RS, Hoy WE, Bertram JF, Black MJ (2011)
Accelerated maturation and abnormal morphology in
the preterm neonatal kidney. J Am Soc Nephrol 22
(7):1365–1374
Sweet D, the working group on prematurity (2007)
European consensus guidelines on the management of
neonatal respiratory distress syndrome. J Perinat Med
35:175–186
Vieux R, Fresson J, Guillemin F et al (2011) Perinatal drug
exposure and renal function in very preterm infants.
Arch Dis Child Fetal Neonatal Ed 96:F290–F295